The broad objective of this proposal is to identify and characterize the most critical molecular sites of interaction between drugs with antipsychotic activity, or potential anti-attention deficit hyperactivity disorder (ADHD) activity, and their G protein-coupled receptor (GPCR) targets. We aim to achieve an understanding of the molecular mechanisms of selective activation by agonists, and inactivation by inverse agonists, as well as the discriminant structural features of neutral antagonists that selectively bind to the D2 and D4 receptors and that are the targets for the drugs used to treat neuropsychiatric disorders. To achieve these objectives, molecular modeling techniques have been employed to predict receptor microdomains that might be interacting with selective and nonselective agonists and antagonists that were docked into rhodopsin-based models of dopamine D2 and D4 receptors. The inferences from these models will be probed with point mutations of the receptor microdomains that appear to be responsible for the functional interactions. In iterative studies, the binding and functional properties of the ligands will be determined in combinedcomputational and experimental protocols to test specific structure-based hypotheses in the mutant and wild type receptor constructs and to relate them to functional outcomes. The results will be interpreted as useful guides for the design of new putative therapeutic agents. The proposed studies will proceed as described in the following series of four interrelated specific aims: 1.) to utilize structural information about high affinity ligands in the structural context ofrhodopsin-based models for dopamine D2 and D4 GPCRs, in order to discriminate receptor microdomains and modes of ligand binding in relation to the agonist versus the antagonist activity of the ligands, 2.) to characterize the manner in which the structures of the ligands relate totheir ability to activate or inactivate dopamine D2 and D4 receptors based on different modes of binding and interaction within identified receptor microdomains, 3.) to determine if certain aromatic 1,4-disubstitutedpiperizine ligands that share an extraordinarily high selectivity for the D4 subtype of dopamine receptor are interacting with a common set of receptor microdomains, and 4.) to apply the combination of molecular models of ligand interaction in dopaminc receptor microdomains and modes of receptor activation, with experimental testing to probe new ligands predicted to have specified effects on D2 and D4 receptors.